Amy Del Medico: Hello, I’m Amy Del Medico and I’m Vice President of Ophthalmology here at Vial. I’m lucky enough to be talking today to Dr. Arshad Khanani and we’re going to be discussing clinical trials and drug development in retinal disease. Dr. Khanani , thank you so much for being with us today.
Arshad Khanani: Thanks, Amy. I’m looking forward to our discussions today.
Amy Del Medico: Thank you. So I was thinking we could kick off with a discussion about geographic atrophy. So last year, there was lots of excitement with Syfovre and Izervay being the first therapies that were approved to treat this disease. What do you think is next for geographic atrophy treatment? And is complement inhibition the only focus?
Arshad Khanani: Amy, that’s a really good question. I’ve been in practice for 14 years and I had patients with geographic atrophy that actually were completely functional with 20-20 vision and over the last decade they went blind and lost all their independence. So having approval of Syfovre and Izervay has been a breakthrough for our patients with geographic atrophy, but we all know that these treatments have modest efficacy and they come with some risk, whether it’s risk of C and V or other things.
And there are differences between those 2 drugs in terms of safety. But as a field, I think we can do better. I think GA is like, now, in an era when we had the thermal laser and PDT laser for neovascular AMD. Where we are stabilizing the disease and slowing down the worsening. And that’s what both of these agents do where we cannot reverse the disease.
We cannot stop the disease, but we are slowing down the worsening. The disease continues to progress. So, in my opinion there are several things as a factor. field that we are looking at. And it’s exciting. First one I think that I’m excited about is AVD-104. It’s a molecule that is a sialic acid mimetic with the dual mechanism of action that inhibits macrophages and also stabilizes the CFH, which is part of the complement system.
So getting back to your question, I think complement system is a key driver of disease, but we know there is inflammation and activated macrophages and the hope is that by targeting dual mechanism, we will be able to hopefully slow the disease better and maybe have some functional benefit as, we have not seen any functional benefit with Syfovre Or Izervay per se.
So, I think as a field we are looking for that. Another one interesting program ARCHER study read out phase 2 is from Annexon, and they have a C1q inhibitor that has shown protection of 3 lines of vision loss. And that program is also moving into phase 3. And as I mentioned, AVD-104 is in phase 2 slash 3 already. Another exciting thing for me as a clinical scientist has been gene therapy. The phase 2 program for JNJ-1887 is also ongoing with a single in clinic, individual gene therapy to slow down GA, but that also works on the complement system. So, I think we are continuing to look at new targets, new delivery methods, moving the field forward in the sense of getting better efficacy outcomes, hopefully some functional visual benefit for our patients with GA with the new programs that are in development currently.
Amy Del Medico: Yeah, I think it will be interesting to see the long term functional data for those two first approved therapies.
Arshad Khanani: Yeah, I mean, I think, in the trials, we have not seen any benefit. Obviously, we are going into the extension studies and continue to look for any benefit there.
And I think, Amy, the issue has been, what are the good testing tools in a busy retina clinic that can actually prove functional benefit in a clinical trial. Many of the programs utilize microperimetry, but I think that is also evolving because many patients with GA, especially central GA cannot do microperimetry well, so I think the microperimetry field is now moving towards a customized grid. Also, more efficient testing. If you’re going to put a patient in a microperimetry machine for 30 to 45 minutes, and they’re struggling. You’re not going to get a good test. And you know that well as leading your CRO about clinical trial design as well as assessments in clinical trials.
And these patients come in, and they’re in clinic for 4 or 5 hours. If you put too many tests, so I think we also are learning that we need to make sure of that. We do this functional test efficiently and accurately so we can actually see a signal. There could be a signal, right? We all know that grows over time and you lose vision and if you slow down, you’re going to slow down vision loss, right?
That’s a very basic concept. I think that the issue mainly is the fact that how do we get that data in a controlled clinical trial setting accurately so that we can actually see the benefit.
Amy Del Medico: Yeah. It’s [00:05:00] always a balance, isn’t it? Between getting as much data as you can and actually making a trial that you can recruit and that is not too much of a burden for patients and we’ll talk a bit about novel endpoints a little bit later on in the interview. But first of all, I was thinking maybe we’d talk a bit about wet AMD. So Obviously, the therapies are diversifying at the moment to include multiple targets such as Type-II and TKI pathways. I know there’s extended release formulations being developed and even gene therapies for wet AMD.
Is there anything that particularly excites you about the future for this particular disease?
Arshad Khanani: I think, we are lucky to have excellent treatment options for our patients with wet AMD and addition of VABYSMO and approval of VABYSMO over years ago with targeting VEGF-A and Ang-2 has been exciting in terms of outcomes when we look at anatomy and disease control and durability, and of course, the recent approval.
Of 8 mg of Aflibercept. And we are still early in our experience with that. But VABYSMO has been out for 2 years. It has better efficacy in terms of anatomic control and durability while having comparable safety to other agents. So that is, to me, the new standard of care for wet AMD. Now, what can we do better?
Right? We still know that we have patients treated with any currently approved agent that need frequent injections and that could be every month, every other month for the rest of their lives. I think durability obviously is something that we are addressing with the programs you mentioned. The 2nd thing though,that doesn’t come into the discussion as much, but I think is equally important is visual acuity gains. We see a ceiling effect in terms of visual acuity gains with VEGF-A suppression or inhibition and, OPT-302 by Opthea is in phase 3 programs, and the data will be reading out middle of next year for the company where we’re inhibiting VEGF-C & D to see if we can get better vision outcomes.
In the phase 2-B trial, there was actually superiority of visual acuity in patients who received Ranibizumab or Lucentis plus OPT-302. So I think there are two unmet needs, durability as well as visual acuity. The only program looking at vision currently in late stages is Opthea’s OPT-302, or the name is Sozinibercept, it’s a tongue twister.
And for durability, we are looking at multiple options, right? So I’m involved with. EYP-1901, I’m involved with OTX, TKI, I’m involved with CLSAX. So all these programs are looking at tyrosine kinase inhibitors. So tyrosine kinase inhibitors have been approved in the oncology space for a while, and what they do is they are Pan-VEGF inhibitors, they work intracellularly.
So the idea is, can we put them in sustained release technology to see if we can actually have a Pan-VEGF inhibition leading to stable disease control and longer term disease control. So the data from DAVIO 2 as well as OTX-TKI phase one has been promising in terms of majority of the patients not needing supplemental treatment for six months or longer at the CLS-AX data from phase one study is also promising and we are waiting for the read out of the phase two odyssey trial. In terms of gene therapy, I think it’s a very exciting space. Personally, for me, I’ve been involved with it for over five years. And I think it’s something that you think that will be sci-fi and not a reality, but it’s becoming a reality where you take a gene for a protein for a common retinal disease, like wet AMD
and you put that gene into the cells of the eye, and then the cells in the eye produce a protein that can inhibit the disease, so, here we have programs with RGX-314 sub retinal programs done in the OR the surgery is they’re in phase three atmosphere, in a sense studies. We have RGX-314 in suprachoroidal space in the AV-8 study.
I recently reported the data from 4150 PRISM study phase two portion where it was compared to Aflibercept in high need patients really showing excellent safety profile while reducing the treatment burden a lot. And then we published recently in the Lancet eClinical Medicine, the data from optic study from Adverum ADVM022 or called Ixo-vec and I recently presented the early look at the Luna study where we are
trying to optimize the steroid prophylaxis. So I think gene therapy will be a reality. It’s just a matter of time in terms of optimizing the prophylaxis using the right vector, the right dose, because we have really good safe agents available currently. So I think programs are moving forward.
4150 is gonna start phase three trials next year in OTX-TKI, in terms of phase 3 has already started the sole study and then EYP-1901, their phase 3 trials are going to start in the future. So I think overall, the [00:10:00] durability treatment burden issue will be addressed in the future and we have multiple shots on goal.
Amy Del Medico: And it is interesting about the gene therapies because I think it wasn’t that long ago that really we were just talking about inherited retinal disease and maybe, dry AMD and it seems to have really taken off quite quickly in terms of research in wet AMD.
Arshad Khanani: Yeah, no, I agree with you, and the data is promising, but I think we need to think of common retinal diseases differently.
We need to think about the fact that we are not replacing a missing gene. We are actually adding a gene for a protein that the eyes are not producing. And now, of course, when you go into common retinal diseases, the safety bar is much higher than an inherited retinal disease where you don’t have a treatment.
So I think that’s what’s evolving over time, but I’m very hopeful that we will likely have an approved gene therapy in the next 3 to 5 years. And I think that’s going to be groundbreaking for the field in terms of having better outcomes, right? Because if you have sustained release of a protein and that’s what you guys are doing, then you will not have fluctuations in anatomy and that may lead to better long term outcomes over time.
As we know that in the real world outcomes are very poor, especially the longer the disease is, the more vision loss we see in these patients. So, yeah, very exciting.
Amy Del Medico: It is, yeah, certainly shake things up if we have a gene therapy for wet AMD. And so I’m going to move on to a question about diabetic retinopathy. So there’s a few companies at the moment developing eye drops for DR, and if those are approved, obviously they’re going to ease the burden of IVT injections for patients. What do you consider to be the most important safety and efficacy considerations specifically for eye drops for diabetic retinopathies?
Arshad Khanani: I think that’s a really good question, Amy. And I think if you look at diabetic retinopathy, right, so I think we should divide into 2 buckets. Number 1 is just diabetic retinopathy without diabetic macular edema. The other 1 is patients with diabetic macular edema. So, let’s address the diabetic retinopathy 1st.
Currently, we have patients with diabetic retinopathy with good vision, especially moderate to severe diabetic retinopathy patients, non-proliferative or NPDR. Those patients respond really well to Anti-VEGF injections, but injections carry a burden. They carry frequency lifetime of treatment. And of course, their risk, because they’re invasive, even though they’re very safe.
There’s a risk of endophthalmitis in 1 to 3 to 5000 patients. So, I think most of us are not treating patients with NPDR even moderate to severe until they get to the proliferative stage where we give them Anti-VEGF and introduce PRP or pan retinal photocoagulation laser. So the unmet need is big here in terms of can we stop the disease or reverse the disease with something that’s not frequent injection.
So you mentioned eye drops, the Ocuphire program is for pills, which is, the data study showed that you can stop diabetic retinopathy. We have Cutera program for eye drops where the trial is ongoing, looking at safety and efficacy of their eyedrop to see if it can stop or reverse diabetic retinopathy via gene therapy that altitude study with RG-314 suprachoroidal, a one time treatment has shown significant benefit for patients in terms of stabilization and not worsening over time and a small subset with 2 step improvements,
but also reducing treatment vision threatening complications of diabetic retinopathy that can happen with untreated disease. So I think the goal is that we can intervene early with an eyedrop or a pill or a gene therapy so that we can stop the vision threatening complications of diabetic macular edema, vitreous hemorrhage, proliferative disease.
I still see tons of patients with diabetic retinopathy in my clinic, they come in legally blind in both eyes and these are patients in their 20s and 30s and even with insurance. So I think there’s a big gap there, Amy and I think it’s a good way to address it with a non invasive treatment or a single time gene therapy.
And then looking at DME we also have a Resolute has a pill, for DME that has a novel mechanism of action that trial is going to read out later this year. We also have OCS-01, which is in stage 2 of the phase 3 diamond study. These are studies looking at eye drops with OCS-01, which is a steroid
eye drop to see if we can benefit patients with DME in terms of visual acuity improvement and OCT improvements and the stage 1 of the phase 3, the data I presented at CTS last year was very promising, in terms of having clinically significant improvements in vision and anatomy compared to a placebo eye drop.
So, I think the holy grail is eye drops or a pill or decrease burden in terms of injections and gene therapy fits in well, and the TKIs actually EYP-1901 and OTX-TKI have ongoing programs in diabetic retinopathy with their treatments to see If we can stabilize or improve diabetic retinopathy.
So, yeah, it’s a big unmet need, and I think a lot of work is being done. Obviously, [00:15:00] we also saw the positive data in the Pavilion study with port delivery system, which is the implant that releases ranibizumab in terms of controlling retinopathy. So, very exciting times for patients with diabetic retinopathy, and hopefully we come up with treatments with less treatment burden or non-invasive nature to help control the disease.
Amy Del Medico: So we’ve talked about unmet need within AMD and diabetic retinopathy, so we haven’t really talked about RVO, but they’re the three main disease areas where drug development has been focused, and obviously that’s because of their high prevalence and hence potential market. But I wondered if there were any other underserved retinal disorders that you’d like to see more options for patients?
Arshad Khanani: I think, RVO naturally comes at the end because it’s a smaller market. I think we discussed wet AMD, which is the biggest market in diabetic retinopathy. And I think addressing durability with multiple programs is great, but we also need to optimize vision, as I said. So I think the future treatments will be multi mechanistic, blocking multiple targets so that we can not only get durability, but hopefully also get better visual acuity.
Amy Del Medico: So I mentioned we were going to talk about novel endpoints and I think it’s quite a hot topic right now. I hear it being spoken about a lot and there’s several innovative technologies that are out there. There’s Novi’s Dark, there’s Adaptive’s sensory technologies, visual function platform.
What’s the general feeling in the retina community about using novel endpoints outside of IRD studies and what should sponsor companies do you think, what should they consider when designing their trials?
Arshad Khanani: I think there’s more and more focus Amy, in terms of functional outcomes, especially when we have these drugs approved without showing functional benefit, even though we know that there is a benefit.
So I think it’s always good to have new technologies. We have used contrast sensitivity system in many of the trials. I think it is being adopted broadly in patients in studies, I think diabetic retinopathy study should implement them too, because there’s a decrease in contrast. So, I think the jury is still out in terms of having a clinically and significant effect in those functional endpoints.
But, yeah I’m really excited about contrast sensitivity, because I actually did contrast sensitivity work when I was in medical school, and I think it’s an end point that was not common at that time but now I think it’s important to look beyond just the visual acuity, which can vary obviously, and which may not show us what we want to see as a functional outcome.
So we need to look at other end points. I don’t have much experience with Novi’s dark technology at this point.
Amy Del Medico: Last question quite a broad question. You’ve obviously got extensive experience in multiple clinical trials. What would you say the key drivers for a site for a retina clinic to recruit patients in what is obviously a very highly competitive
landscape?
Arshad Khanani: I think the key for me as a site is what is a new treatment gonna do to the patient that’s sitting in front of me? And I would like to treat them as a family member. So I don’t participate in biosimilar trials. I wanna move the field forward. So anything that has the potential to be better, than standard of care.
Anything that has an unmet need that we don’t have a treatment for are the studies that we are interested in participating in. So I think it’s for sponsors. The studies that actually bring novel technology, novel treatment options, let’s say TKIs, gene therapy, hopefully better vision with AVD-104, things like that recruit much faster versus a trial that is doing more of the same, or even less than what the standard of care is.
So, I think that’s 1 and number 2 is, I think studies need to be designed wisely. They have to have sites and patients in mind. And, of course, using a CRO that actually cares about sites. Vial has been a CRO for many of our trials now, even early stage, and I love the communication with you and the team as well as using the latest technology for EDC and other things to make the burden less for sites and sponsors.
So, I think it’s a combination of things. A company with good science, moving the field forward, a good team, a good CRO and then, of course, a good site. I think those are the things that are important for sponsors to consider as they bring these novel treatments.
Amy Del Medico: Fantastic. Dr. Kanani, thank you so much.
It’s always a pleasure speaking with you.
Arshad Khanani: Thank you, Amy. I enjoyed our discussions. Thank you.
